The overall goal of this proposal is to develop novel approaches in delivery of antigens and adjuvants with biomaterials and to investigate host responses in response to these new vaccines, with the ultimate goal to develop successful vaccines and therapeutic interventions against infectious diseases. The K22 award will help me by providing the initial support necessary to gain additional training and mentoring and establish my research career as an independent investigator. Vaccination remains one of the most effective medical interventions against infectious diseases. However, vaccine adjuvants currently used in clinics are poor activators of cytotoxic cellular immune responses. To address this, we have recently developed a novel class of lipid-based nanoparticulate system that can co-entrap antigen and adjuvant and efficiently deliver them to antigen presenting cells. These synthetic vesicles enhanced cross-presentation of protein antigens, inducing massively expanded CD8+ T cell responses, substantially stronger than any other previously reported protein vaccines, to the best of our knowledge. In addition, ICMVs loaded with candidate malaria antigen also elicited significantly higher antibody titers with greater avidity, compared with immunization with currently licensed adjuvants. These results indicate that these antigen/adjuvant-carrying ICMVs form an extremely potent whole-protein vaccine. However, what is not fully known in the author's studies and also in the literature is the expansion and trafficking patterns of antigen-specific T cells at whole-animal level in response to particle vaccination. Preliminary studies have shown that particles that efficiently drain to lymph nodes promoted expansion and maintenance of antigen-specific CD8+ T cells at draining lymph nodes, whereas particles that remain deposited at injection site with reduced draining efficiency promoted accumulation of antigen- experienced CD8+ T cells at the particle injection site for an extended period. This proposal aims to investigate the relationship between tissue distribution of vaccine particles and trafficking patterns of T cells and to develop a vaccine platform that can exploit this particle-mediated host cellular response toward tissue-specific immunity. The specific aims are (1) Can we control the trafficking patterns of antigen-specific T cells in vivo and establish tissue-specific memory T cells using pathogen-mimicking particles deposited in tissues? And can we utilize this approach to induce immunity against influenza virus? (2) Can we develop infection- mimicking materials using ICMVs loaded in injectable gels and apply this new vaccine delivery approach to confer long-term memory response in mucosal tissues? The results from these studies will help to identify factors governing trafficking patterns of T cells following particle immunization, and may lead to a vaccine platform that could be applied to numerous other infectious diseases. Public Health Relevance: The results obtained from these proposed studies may lead to development of a vaccine platform that can elicit potent cellular immune responses and control the distribution of antigen-specific T cells. Such vaccine platform could be applied as novel vaccination strategies against infectious diseases and would have a major impact on public health.